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Modulation of Voltage-Gated Sodium Channel (VGSC) Activity in Human Dorsal Root Ganglion (DRG) Neurons by Herpesvirus Quiescent Infection

Qiaojuan Zhang, Feng Chen, Miguel Martin-Caraballo, View ORCID ProfileShaochung V. Hsia
doi: https://doi.org/10.1101/714691
Qiaojuan Zhang
Department of Pharmaceutical Sciences, School of Pharmacy and Health Professions, University of Maryland Eastern Shore, Princess Anne, MD 21853
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Feng Chen
Department of Pharmaceutical Sciences, School of Pharmacy and Health Professions, University of Maryland Eastern Shore, Princess Anne, MD 21853
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Miguel Martin-Caraballo
Department of Pharmaceutical Sciences, School of Pharmacy and Health Professions, University of Maryland Eastern Shore, Princess Anne, MD 21853
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Shaochung V. Hsia
Department of Pharmaceutical Sciences, School of Pharmacy and Health Professions, University of Maryland Eastern Shore, Princess Anne, MD 21853
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  • ORCID record for Shaochung V. Hsia
  • For correspondence: vhsia@umes.edu
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Abstract

The molecular mechanisms of pain associated with alphaherpesvirus latency are not clear. We hypothesize that the voltage-gated sodium channels (VGSC) on dorsal root ganglion (DRG) neurons controlling electrical impulses may have abnormal activity during viral latent infection and reactivation. We used HSV-1 to infect human DRG-derived neuronal cell line HD10.6 to study viral latency establishment, maintenance and reactivation as well as changes of VGSC functional expression. Differentiated cells exhibited robust tetrodotoxin (TTX) sensitive sodium currents and acute infection significantly reduced the VGSC functional expression within 24 hours, and completely abolished the VGSC activity within three days lytic infection. A quiescent state of infection mimicking latency can be achieved by HSV infection in the presence of acyclovir (ACV) for 7 days followed by 5 days of ACV washout and the viruses can remain dormant for another three weeks. It was noted that during HSV-1 latency establishment, the loss of VGSC activity caused by HSV-1 infection could not be blocked by ACV treatment within 3 days infection. However, neurons with continued treatment of ACV for another 4 days showed a gradual recovery of VGSC functional expression. Furthermore, the latent neurons exhibited higher VGSC activity in comparison to controls. The overall regulation of VGSC by HSV-1 during its quiescent infection was proved by increased transcription and possible translation of Nav1.7. Together these observations demonstrated a very complex pattern of electrophysiological changes during HSV infection of DRG neurons, which may have implication for understanding the mechanisms of virus-mediated pain linked to latency and reactivation.

Importance The reactivation of the herpesvirus from ganglionic neurons may cause cranial nerve disorders and unbearable pain. It is unclear why normal stimuli would trigger enhanced pain sensation in these patients. The current work meticulously studies the functional expression profile changes of VGSC during the process of latency establishment using an in vitro model. Our results indicated that VGSC activity was eliminated upon infection but steadily recovered during the latency establishment and the latent neurons exhibited even higher VGSC activity. This finding advances our knowledge of how ganglion neurons generated uncharacteristic electrical impulses due to abnormal VGSC functional expression influenced by latent virus.

Footnotes

  • Abbreviation: HSV-1, Herpes Simplex Virus Type-1; VGSC, Voltage Gated Sodium Channel; qPCR, quantitative Polymerase Chain Reaction; DRG, Dorsal Root Ganglion; TG, Trigeminal Ganglia; ACV, Acyclovir; TTX, tetrodotoxin; TSA, Trichostatin A; dpi, Days Post Infection; HDAC, histone deacetylase; PPIA, peptidylprolyl isomerase A; LAT, Latency Associate Transcript; TK, thymidine kinase; GFP, green fluorescent protein; M-GFP, HSV-1 strain McKrae/GFP; PI3K, Phosphoinositide 3-kinase

  • DISCLOSURE STATEMENT: The authors have nothing to disclose.

Copyright 
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Posted July 25, 2019.
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Modulation of Voltage-Gated Sodium Channel (VGSC) Activity in Human Dorsal Root Ganglion (DRG) Neurons by Herpesvirus Quiescent Infection
Qiaojuan Zhang, Feng Chen, Miguel Martin-Caraballo, Shaochung V. Hsia
bioRxiv 714691; doi: https://doi.org/10.1101/714691
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Modulation of Voltage-Gated Sodium Channel (VGSC) Activity in Human Dorsal Root Ganglion (DRG) Neurons by Herpesvirus Quiescent Infection
Qiaojuan Zhang, Feng Chen, Miguel Martin-Caraballo, Shaochung V. Hsia
bioRxiv 714691; doi: https://doi.org/10.1101/714691

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